bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2024‒11‒03
twelve papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Progressive plasticity during colorectal cancer metastasis.
  2. A comprehensive transcriptome characterization of individual nuclear receptor pathways in the human small intestine.
  3. Polyclonality overcomes fitness barriers in Apc-driven tumorigenesis.
  4. Nutrient-sensing alteration leads to age-associated distortion of intestinal stem cell differentiating direction.
  5. When molecular biology transforms clinical oncology: the EGFR journey in colorectal cancer.
  6. Spatiotemporal lineage tracing reveals the dynamic spatial architecture of tumor growth and metastasis.
  7. GPA33 expression in colorectal cancer can be induced by WNT inhibition and targeted by cellular therapy.
  8. Stemness in solid malignancies: coping with immune attack.
  9. HOXB8 mediates resistance to cetuximab in colorectal cancer cells through activation of the STAT3 pathway.
  10. Multiomic analysis of familial adenomatous polyposis reveals molecular pathways associated with early tumorigenesis.
  11. Global loss of promoter-enhancer connectivity and rebalancing of gene expression during early colorectal cancer carcinogenesis.
  12. Polyclonal-to-monoclonal transition in colorectal precancerous evolution.
  1. Nature. 2024 Oct 30.
    Progressive plasticity during colorectal cancer metastasis.
    A R Moorman, E K Benitez, F Cambuli, Q Jiang, A Mahmoud, M Lumish, S Hartner, S Balkaran, J Bermeo, S Asawa, C Firat, A Saxena, F Wu, A Luthra, C Burdziak, Y Xie, V Sgambati, K Luckett, Y Li, Z Yi, I Masilionis, K Soares, E Pappou, R Yaeger, P Kingham, W Jarnagin, P Paty, M R Weiser, L Mazutis, M D'Angelica, J Shia, J Garcia-Aguilar, T Nawy, T J Hollmann, R Chaligné, F Sanchez-Vega, R Sharma, D Pe'er, K Ganesh.
      As cancers progress, they become increasingly aggressive-metastatic tumours are less responsive to first-line therapies than primary tumours, they acquire resistance to successive therapies and eventually cause death1,2. Mutations are largely conserved between primary and metastatic tumours from the same patients, suggesting that non-genetic phenotypic plasticity has a major role in cancer progression and therapy resistance3-5. However, we lack an understanding of metastatic cell states and the mechanisms by which they transition. Here, in a cohort of biospecimen trios from same-patient normal colon, primary and metastatic colorectal cancer, we show that, although primary tumours largely adopt LGR5+ intestinal stem-like states, metastases display progressive plasticity. Cancer cells lose intestinal cell identities and reprogram into a highly conserved fetal progenitor state before undergoing non-canonical differentiation into divergent squamous and neuroendocrine-like states, a process that is exacerbated in metastasis and by chemotherapy and is associated with poor patient survival. Using matched patient-derived organoids, we demonstrate that metastatic cells exhibit greater cell-autonomous multilineage differentiation potential in response to microenvironment cues compared with their intestinal lineage-restricted primary tumour counterparts. We identify PROX1 as a repressor of non-intestinal lineage in the fetal progenitor state, and show that downregulation of PROX1 licenses non-canonical reprogramming.
    DOI:  https://doi.org/10.1038/s41586-024-08150-0
  2. Proc Natl Acad Sci U S A. 2024 Nov 05. 121(45): e2411189121
    A comprehensive transcriptome characterization of individual nuclear receptor pathways in the human small intestine.
    Sam Willemsen, Fjodor A Yousef Yengej, Jens Puschhof, Maarten B Rookmaaker, Marianne C Verhaar, Johan van Es, Joep Beumer, Hans Clevers.
      Nuclear receptors (NRs) are widely expressed transcription factors that bind small, lipophilic compounds and regulate diverse biological processes. In the small intestine, NRs are known to act as sensors that control transcriptional responses to endogenous and exogenous signals, yet their downstream effects have not been characterized extensively. Here, we investigate the activation of six different NRs individually in human intestinal organoids using small molecules agonists. We observe changes in key enterocyte functions such as lipid, glucose, and amino acid absorption, the regulation of electrolyte balance, and drug metabolism. Our findings reinforce PXR, LXR, FXR, and PPARα as regulators of lipid absorption. Furthermore, known hepatic effects of AHR and VDR activation were recapitulated in the human small intestine. Finally, we identify unique target genes for intestinal PXR activation (ERG28, TMEM97, and TM7SF2), LXR activation (RAB6B), and VDR activation (CA12). This study provides an unbiased and comprehensive transcriptomic description of individual NR pathways in the human small intestine. By gaining a deeper understanding of the effects of individual NRs, we might better harness their pharmacological and therapeutic potential.
    Keywords:  lipid absorption; nuclear receptors; organoids; small intestine
    DOI:  https://doi.org/10.1073/pnas.2411189121
  3. Nature. 2024 Oct;634(8036): 1196-1203
    Polyclonality overcomes fitness barriers in Apc-driven tumorigenesis.
    Iannish D Sadien, Sam Adler, Shenay Mehmed, Sasha Bailey, Ashley Sawle, Dominique-Laurent Couturier, Matthew Eldridge, David J Adams, Richard Kemp, Filipe C Lourenço, Douglas J Winton.
      Loss-of-function mutations in the tumour suppressor APC are an initial step in intestinal tumorigenesis1,2. APC-mutant intestinal stem cells outcompete their wild-type neighbours through the secretion of Wnt antagonists, which accelerates the fixation and subsequent rapid clonal expansion of mutants3-5. Reports of polyclonal intestinal tumours in human patients and mouse models appear at odds with this process6,7. Here we combine multicolour lineage tracing with chemical mutagenesis in mice to show that a large proportion of intestinal tumours have a multiancestral origin. Polyclonal tumours retain a structure comprising subclones with distinct Apc mutations and transcriptional states, driven predominantly by differences in KRAS and MYC signalling. These pathway-level changes are accompanied by profound differences in cancer stem cell phenotypes. Of note, these findings are confirmed by introducing an oncogenic Kras mutation that results in predominantly monoclonal tumour formation. Further, polyclonal tumours have accelerated growth dynamics, suggesting a link between polyclonality and tumour progression. Together, these findings demonstrate the role of interclonal interactions in promoting tumorigenesis through non-cell autonomous pathways that are dependent on the differential activation of oncogenic pathways between clones.
    DOI:  https://doi.org/10.1038/s41586-024-08053-0
  4. Nat Commun. 2024 Oct 25. 15(1): 9243
    Nutrient-sensing alteration leads to age-associated distortion of intestinal stem cell differentiating direction.
    Zihua Yu, Yuedan Zhu, Yi Chen, Chenxi Feng, Zehong Zhang, Xiaoxin Guo, Haiou Chen, Xingzhu Liu, Yu Yuan, Haiyang Chen.
      Nutrient-sensing pathways undergo deregulation in aged animals, exerting a pivotal role in regulating the cell cycle and subsequent stem cell division. Nevertheless, their precise functions in governing pluripotent stem cell differentiation remain largely elusive. Here, we uncovered a significant alteration in the cellular constituents of the intestinal epithelium in aged humans and mice. Employing Drosophila midgut and mouse organoid culture models, we made an observation regarding the altered trajectory of differentiation in intestinal stem cells (ISC) during overnutrition or aging, which stems from the erroneous activation of the insulin receptor signaling pathway. Through genetic analyses, we ascertained that the nutrient-sensing pathway regulated the direction of ISC differentiation by modulating the maturation of endosomes and SOX21A transcription factor. This study elucidates a nutrient-sensing pathway-mediated mechanism underlying stem cell differentiation, offering insights into the etiology of stem cell dysfunction in aged animals, including humans.
    DOI:  https://doi.org/10.1038/s41467-024-53675-7
  5. Mol Oncol. 2024 Oct 29.
    When molecular biology transforms clinical oncology: the EGFR journey in colorectal cancer.
    Pietro Paolo Vitiello, Nadia Saoudi González, Alberto Bardelli.
      The discovery of growth factors and their involvement in cancer represents the foundation of precision oncology. The preclinical and clinical development of agents targeting epidermal growth factor receptor (EGFR) in colorectal cancer (CRC) were accompanied by big hype and hopes, though the clinical testing of such agents clashed with intrinsic and acquired resistance, greatly limiting their therapeutic value. However, a better understanding of the biology of the EGFR signaling pathway in CRC, coupled with the development of liquid biopsy methodologies to study cancer evolution in real time, fostered the clinical refinement of anti-EGFR treatment in CRC. Such a workflow, based on the co-evolution of biology knowledge and clinical development, allowed to couple the discovery of relevant therapy resistance mechanisms to the development of strategies to bypass this resistance. A broader application of this paradigm could prove successful and create an effective shortcut between the bench and the bedside for treatment strategies other than targeted therapy.
    Keywords:  EGFR; colorectal cancer; drug resistance; precision medicine; translational research
    DOI:  https://doi.org/10.1002/1878-0261.13754
  6. bioRxiv. 2024 Oct 24. pii: 2024.10.21.619529. [Epub ahead of print]
    Spatiotemporal lineage tracing reveals the dynamic spatial architecture of tumor growth and metastasis.
    Matthew G Jones, Dawei Sun, Kyung Hoi Joseph Min, William N Colgan, Luyi Tian, Jackson A Weir, Victor Z Chen, Luke W Koblan, Kathryn E Yost, Nicolas Mathey-Andrews, Andrew J C Russell, Robert R Stickels, Karol S Balderrama, William M Rideout, Howard Y Chang, Tyler Jacks, Fei Chen, Jonathan S Weissman, Nir Yosef, Dian Yang.
      Tumor progression is driven by dynamic interactions between cancer cells and their surrounding microenvironment. Investigating the spatiotemporal evolution of tumors can provide crucial insights into how intrinsic changes within cancer cells and extrinsic alterations in the microenvironment cooperate to drive different stages of tumor progression. Here, we integrate high-resolution spatial transcriptomics and evolving lineage tracing technologies to elucidate how tumor expansion, plasticity, and metastasis co-evolve with microenvironmental remodeling in a Kras;p53 -driven mouse model of lung adenocarcinoma. We find that rapid tumor expansion contributes to a hypoxic, immunosuppressive, and fibrotic microenvironment that is associated with the emergence of pro-metastatic cancer cell states. Furthermore, metastases arise from spatially-confined subclones of primary tumors and remodel the distant metastatic niche into a fibrotic, collagen-rich microenvironment. Together, we present a comprehensive dataset integrating spatial assays and lineage tracing to elucidate how sequential changes in cancer cell state and microenvironmental structures cooperate to promote tumor progression.
    DOI:  https://doi.org/10.1101/2024.10.21.619529
  7. Oncogene. 2024 Oct 29.
    GPA33 expression in colorectal cancer can be induced by WNT inhibition and targeted by cellular therapy.
    Teresa Börding, Tobias Janik, Philip Bischoff, Markus Morkel, Christine Sers, David Horst.
      GPA33 is a promising surface antigen for targeted therapy in colorectal cancer (CRC). It is expressed almost exclusively in CRC and intestinal epithelia. However, previous clinical studies have not achieved expected response rates. We investigated GPA33 expression and regulation in CRC and developed a GPA33-targeted cellular therapy. We examined GPA33 expression in CRC cohorts using immunohistochemistry and immunofluorescence. We analyzed GPA33 regulation by interference with oncogenic signaling in vitro and in vivo using inhibitors and conditional inducible regulators. Furthermore, we engineered anti-GPA33-CAR T cells and assessed their activity in vitro and in vivo. GPA33 expression showed consistent intratumoral heterogeneity in CRC with antigen loss at the infiltrative tumor edge. This pattern was preserved at metastatic sites. GPA33-positive cells had a differentiated phenotype and low WNT activity. Low GPA33 expression levels were linked to tumor progression in patients with CRC. Downregulation of WNT activity induced GPA33 expression in vitro and in GPA33-negative tumor cell subpopulations in xenografts. GPA33-CAR T cells were activated in response to GPA33 and reduced xenograft growth in mice after intratumoral application. GPA33-targeted therapy may be improved by simultaneous WNT inhibition to enhance GPA33 expression. Furthermore, GPA33 is a promising target for cellular immunotherapy in CRC.
    DOI:  https://doi.org/10.1038/s41388-024-03200-3
  8. Nat Rev Cancer. 2024 Oct 25.
    Stemness in solid malignancies: coping with immune attack.
    Judith Agudo, Yuxuan Miao.
      Immunotherapy has become a key new pillar of cancer treatment, and this has sparked interest in understanding mechanisms of cancer immune evasion. It has long been appreciated that cancers are constituted by heterogeneous populations of tumour cells. This feature is often fuelled by specialized cells that have molecular programs resembling tissue stem cells. Although these cancer stem cells (CSCs) have capacity for unlimited self-renewal and differentiation, it is increasingly evident that some CSCs are capable of achieving remarkable immune resistance. Given that most immunotherapy regiments have overlooked CSC-specific immune-evasive mechanisms, many current treatment strategies often lead to cancer relapse. This Review focuses on advancements in understanding how CSCs in solid tumours achieve their unique immune-evasive properties, enabling them to drive tumour regrowth. Moreover, as cancers often arise from tissue stem cells that acquired oncogenic mutations, we discuss how tissue stem cells undergoing malignant transformation activate intrinsic immune-evasive mechanisms and establish close interactions with suppressive immune cells to escape immune surveillance. In addition, we summarize how in advanced disease stages, CSCs often hijack features of normal stem cells to resist antitumour immunity. Finally, we provide insights in how to design a new generation of cancer immunotherapies to ensure elimination of CSCs.
    DOI:  https://doi.org/10.1038/s41568-024-00760-0
  9. Discov Oncol. 2024 Oct 29. 15(1): 603
    HOXB8 mediates resistance to cetuximab in colorectal cancer cells through activation of the STAT3 pathway.
    Yunan Liang, Han Lin, Zongsheng Jiang, Qi Zhao, Ri Cui, Shaotang Li.
      Homeobox B8 (HOXB8) belongs to the HOX family and was essential to the development of colorectal carcinoma. Among the prevalent monoclonal antibodies for treating RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients, cetuximab stands out, but resistance to cetuximab frequently arises in targeted treatments. Currently, the role of HOXB8 in cetuximab-resistant mCRC remains unclear. By comparing drug-sensitive cell lines (SW48) with drug-resistant cell lines (HCT116, CACO2), we discovered that HOXB8 was substantially expressed in cetuximab-resistant cell lines, and furthermore, in drug-resistant cell lines (HCT116, CACO2), HOXB8 knockdown increased the cytotoxicity of cetuximab via blocking the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Conversely, the excessive expression of HOXB8 reduced the growth suppression in SW48 cells caused by cetuximab by triggering the STAT3 signaling pathway. Conclusively, we conclude that HOXB8 has played an essential role in cetuximab-resistant mCRC and that treating HOXB8 specifically may be a useful treatment approach for certain cetuximab-resistant mCRC patients.
    DOI:  https://doi.org/10.1007/s12672-024-01440-z
  10. Nat Cancer. 2024 Oct 30.
    Multiomic analysis of familial adenomatous polyposis reveals molecular pathways associated with early tumorigenesis.
    Edward D Esplin, Casey Hanson, Si Wu, Aaron M Horning, Nasim Barapour, Stephanie A Nevins, Lihua Jiang, Kévin Contrepois, Hayan Lee, Tuhin K Guha, Zheng Hu, Rozelle Laquindanum, Meredith A Mills, Hassan Chaib, Roxanne Chiu, Ruiqi Jian, Joanne Chan, Mathew Ellenberger, Winston R Becker, Bahareh Bahmani, Aziz Khan, Basil Michael, Annika K Weimer, D Glen Esplin, Jeanne Shen, Samuel Lancaster, Emma Monte, Thomas V Karathanos, Uri Ladabaum, Teri A Longacre, Anshul Kundaje, Christina Curtis, William J Greenleaf, James M Ford, Michael P Snyder.
      Familial adenomatous polyposis (FAP) is a genetic disease causing hundreds of premalignant polyps in affected persons and is an ideal model to study transitions of early precancer states to colorectal cancer (CRC). We performed deep multiomic profiling of 93 samples, including normal mucosa, benign polyps and dysplastic polyps, from six persons with FAP. Transcriptomic, proteomic, metabolomic and lipidomic analyses revealed a dynamic choreography of thousands of molecular and cellular events that occur during precancerous transitions toward cancer formation. These involve processes such as cell proliferation, immune response, metabolic alterations (including amino acids and lipids), hormones and extracellular matrix proteins. Interestingly, activation of the arachidonic acid pathway was found to occur early in hyperplasia; this pathway is targeted by aspirin and other nonsteroidal anti-inflammatory drugs, a preventative treatment under investigation in persons with FAP. Overall, our results reveal key genomic, cellular and molecular events during the earliest steps in CRC formation and potential mechanisms of pharmaceutical prophylaxis.
    DOI:  https://doi.org/10.1038/s43018-024-00831-z
  11. Nat Cancer. 2024 Oct 30.
    Global loss of promoter-enhancer connectivity and rebalancing of gene expression during early colorectal cancer carcinogenesis.
    Yizhou Zhu, Hayan Lee, Shannon White, Annika K Weimer, Emma Monte, Aaron Horning, Stephanie A Nevins, Edward D Esplin, Kristina Paul, Gat Krieger, Zohar Shipony, Roxanne Chiu, Rozelle Laquindanum, Thomas V Karathanos, Melissa W Y Chua, Meredith Mills, Uri Ladabaum, Teri Longacre, Jeanne Shen, Ariel Jaimovich, Doron Lipson, Anshul Kundaje, William J Greenleaf, Christina Curtis, James M Ford, Michael P Snyder.
      Although three-dimensional (3D) genome architecture is crucial for gene regulation, its role in disease remains elusive. We traced the evolution and malignant transformation of colorectal cancer (CRC) by generating high-resolution chromatin conformation maps of 33 colon samples spanning different stages of early neoplastic growth in persons with familial adenomatous polyposis (FAP). Our analysis revealed a substantial progressive loss of genome-wide cis-regulatory connectivity at early malignancy stages, correlating with nonlinear gene regulation effects. Genes with high promoter-enhancer (P-E) connectivity in unaffected mucosa were not linked to elevated baseline expression but tended to be upregulated in advanced stages. Inhibiting highly connected promoters preferentially represses gene expression in CRC cells compared to normal colonic epithelial cells. Our results suggest a two-phase model whereby neoplastic transformation reduces P-E connectivity from a redundant state to a rate-limiting one for transcriptional levels, highlighting the intricate interplay between 3D genome architecture and gene regulation during early CRC progression.
    DOI:  https://doi.org/10.1038/s43018-024-00823-z
  12. Nature. 2024 Oct 30.
    Polyclonal-to-monoclonal transition in colorectal precancerous evolution.
    Zhaolian Lu, Shanlan Mo, Duo Xie, Xiangwei Zhai, Shanjun Deng, Kantian Zhou, Kun Wang, Xueling Kang, Hao Zhang, Juanzhen Tong, Liangzhen Hou, Huijuan Hu, Xuefei Li, Da Zhou, Leo Tsz On Lee, Li Liu, Yaxi Zhu, Jing Yu, Ping Lan, Jiguang Wang, Zhen He, Xionglei He, Zheng Hu.
      Unravelling the origin and evolution of precancerous lesions is crucial for effectively preventing malignant transformation, yet our current knowledge remains limited1-3. Here we used a base editor-enabled DNA barcoding system4 to comprehensively map single-cell phylogenies in mouse models of intestinal tumorigenesis induced by inflammation or loss of the Apc gene. Through quantitative analysis of high-resolution phylogenies including 260,922 single cells from normal, inflamed and neoplastic intestinal tissues, we identified tens of independent cell lineages undergoing parallel clonal expansions within each lesion. We also found polyclonal origins of human sporadic colorectal polyps through bulk whole-exome sequencing and single-gland whole-genome sequencing. Genomic and clinical data support a model of polyclonal-to-monoclonal transition, with monoclonal lesions representing a more advanced stage. Single-cell RNA sequencing revealed extensive intercellular interactions in early polyclonal lesions, but there was significant loss of interactions during monoclonal transition. Therefore, our data suggest that colorectal precancer is often founded by many different lineages and highlight their cooperative interactions in the earliest stages of cancer formation. These findings provide insights into opportunities for earlier intervention in colorectal cancer.
    DOI:  https://doi.org/10.1038/s41586-024-08133-1
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