bims-istrec 2022-06-05 papers

Small. 2022 May 29. e2201585

Synergistic Lysosomal Impairment and ER Stress Activation for Boosted Autophagy Dysfunction Based on Te Double-Headed Nano-Bullets.

Tingting Wang, Guangxu Xiao, Qianglan Lu, Yue Zhou, Siyu Wang, Xiaoyang Liang, Yilin Song, Min Xu, Yan Zhu, Nan Li.

To overcome the autophagy compromised mechanism of protective cellular processes by "eating"/"digesting" damaged organelles or potentially toxic materials with autolysosomes in tumor cells, lysosomal impairment can be utilized as a traditional autophagy dysfunction route for tumor therapy; however, this conventional one-way autophagy dysfunction approach is always limited by the therapeutic efficacy. Herein, an innovative pharmacological strategy that can excessively provoke autophagy via endoplasmic reticulum (ER) stress is implemented along with lysosomal impairment to enhance autophagy dysfunction. In this work, the prepared tellurium double-headed nanobullets (TeDNBs) with controllable morphology are modified with human serum albumin (HSA) which facilitates internalization by tumor cells. On the one hand, ER stress can be stimulated by upregulating the phosphorylation eukaryotic translation initiation factor 2 (P-eIF2α) owing to the production of tellurite (TeO3 2- ) in the specifical hydrogen peroxide-rich tumor environment; thus, autophagy overstimulation occurs. On the other hand, OME can deacidify and impair lysosomes by downregulating lysosomal-associated membrane protein 1 (LAMP1), therefore blocking autolysosome formation. Both in vitro and in vivo results demonstrate that the synthesized TeDNBs-HSA/OME (TeDNBs-HO) exhibit excellent therapeutic efficacy by autophagy dysfunction through ER stress induction and lysosomal damnification. Thus, TeDNBs-HO is verified to be a promising theranostic nanoagent for effective tumor therapy.

Keywords: Te double-headed nanobullets; boosted autophagy dysfunction; endoplasmic reticulum stress activation; lysosomal impairment; omeprazole

DOI: https://doi.org/10.1002/smll.202201585

Nat Cancer. 2022 Jun 02.

Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress.

Triple-negative breast cancer (TNBC) has a poor clinical outcome, due to a lack of actionable therapeutic targets. Herein we define lysosomal acid lipase A (LIPA) as a viable molecular target in TNBC and identify a stereospecific small molecule (ERX-41) that binds LIPA. ERX-41 induces endoplasmic reticulum (ER) stress resulting in cell death, and this effect is on target as evidenced by specific LIPA mutations providing resistance. Importantly, we demonstrate that ERX-41 activity is independent of LIPA lipase function but dependent on its ER localization. Mechanistically, ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding. This targeted vulnerability has a large therapeutic window, with no adverse effects either on normal mammary epithelial cells or in mice. Our study implicates a targeted strategy for solid tumors, including breast, brain, pancreatic and ovarian, whereby small, orally bioavailable molecules targeting LIPA block protein folding, induce ER stress and result in tumor cell death.

DOI: https://doi.org/10.1038/s43018-022-00389-8

Nat Cell Biol. 2022 Jun 02.

A stromal Integrated Stress Response activates perivascular cancer-associated fibroblasts to drive angiogenesis and tumour progression.

Bidirectional signalling between the tumour and stroma shapes tumour aggressiveness and metastasis. ATF4 is a major effector of the Integrated Stress Response, a homeostatic mechanism that couples cell growth and survival to bioenergetic demands. Using conditional knockout ATF4 mice, we show that global, or fibroblast-specific loss of host ATF4, results in deficient vascularization and a pronounced growth delay of syngeneic melanoma and pancreatic tumours. Single-cell transcriptomics of tumours grown in Atf4Δ/Δ mice uncovered a reduction in activation markers in perivascular cancer-associated fibroblasts (CAFs). Atf4Δ/Δ fibroblasts displayed significant defects in collagen biosynthesis and deposition and a reduced ability to support angiogenesis. Mechanistically, ATF4 regulates the expression of the Col1a1 gene and levels of glycine and proline, the major amino acids of collagen. Analyses of human melanoma and pancreatic tumours revealed a strong correlation between ATF4 and collagen levels. Our findings establish stromal ATF4 as a key driver of CAF functionality, malignant progression and metastasis.

DOI: https://doi.org/10.1038/s41556-022-00918-8

Angew Chem Int Ed Engl. 2022 Jun 01.

Restoration of the Immunogenicity of Tumor Cells for Enhanced Cancer Therapy via Nanoparticle-Mediated Copper Chaperone Inhibition.

Feixiang Ding, Fei Li, Dongsheng Tang, Bin Wang, Junyan Liu, Xiaoyuan Mao, Jiye Yin, Haihua Xiao, Jing Wang, Zhaoqian Liu.

Recent progress in studying copper-dependent targets and pathways in the context of tumor treatment has provided new insights into therapeutic strategies of leveraging copper-dependent disease vulnerabilities and pharmacologically manipulation of intratumor copper transportation to improve chemotherapy. Here, we developed ROS-sensitive nanoparticles loaded with copper chaperone inhibitor DC_AC50 and cisplatin(IV) prodrug. The released DC_AC50 can promote a remarkable accumulation of intracellular cisplatin and copper through inhibition of the Atox1-ATPase pathways, thereby enhancing the chemotherapeutic effect of cisplatin and inducing significant ROS generation. Excessive ROS then elicit intense endoplasmic reticulin (ER) stress which facilitates the immunogenic cell death (ICD) spurring a sustained immune response. Our study suggests that nanoparticle-mediated copper chaperone inhibition via DC_AC50 can restore the immunogenicity of tumor cells for enhanced chemotherapy and cancer immunotherapy.

Keywords: Copper chaperone inhibition * Immunogenic cell death * Nanoparticles * Platinum * ROS-based ER stress

DOI: https://doi.org/10.1002/anie.202203546