Extracellular Matrix Sensing Controls Autophagy in Pancreatic Cancer

Heterogeneity in the pancreatic ductal adenocarcinoma (PDAC) microenvironment is associated with poor prognosis, yet how autophagic heterogeneity contributes to disease progression remains unclear. In this study, Assi and colleagues investigated the role of non-metabolic autophagic flux in PDAC. Compared to cells 2D monolayer culture, cells in 3D spheroids and orthotopic tumors exhibited various levels of autophagic flux. CRISPR–Cas9 knockout screens and rescue experiments conducted under nutrient deprivation revealed that depletion of NF2 and MAP4K4 decreased lysosome function and reduced autophagy, indicating that upstream Hippo pathway components promote autophagic flux. Accordingly, constitutive activation of the Hippo transcriptional repressor YAP1 was determined to be both necessary and sufficient to suppress autophagy. Interactions between YAP1, TEAD4, and the NCOR repressive complex led to reduction of acetylation of lysine 27 of histone 3 (H3K27ac) levels on autophagy and lysosome genes, inhibiting their expression. Moreover, NF2 deletion increased cell death in 3D, but not 2D, culture and suppressed the growth of orthotopic tumors, demonstrating the role of autophagic flux in PDAC cellular fitness and survival. Low-autophagy cells showed increases in YAP1 activation, proliferation, and proximity to the stroma in samples from patients with PDAC, forming larger tumors than high-autophagy cells in xenograft experiments. Depletion of the extracellular matrix (ECM) increased autophagic flux in PDAC cells, which showed preferential binding to laminin over fibronectin and vitronectin. While several integrins were highly expressed on the surface of PDAC cells, only knockdown of integrinα3 (ITGA3) promoted autophagy and decreased autophagic heterogeneity. Mechanistically, ITGA3 was shown to reduce YAP1 activation by enhancing YAP1 protein degradation. Finally, treatment with anti-ITGA3 neutralizing antibodies enhanced the growth-suppressing effects of the autophagy flux inhibitor hydroxychloroquine in 3D systems by targeting high-autophagy cells. The addition of gemcitabine chemotherapy, which targeted low-autophagy cells, further inhibited PDAC tumor growth. Altogether, this study sheds light on the role of ECM sensing in the regulation of autophagy heterogeneity and proposes a novel combination strategy that targets autophagic heterogeneity in PDAC.Assi M, Wang R, Kawaler EA, Sohn ASW, Dewan MZ, Kalfakakou D, et al. Extracellular matrix sensing regulates intratumoral heterogeneity of autophagic flux. Cell 2026 Feb 16 Epub ahead of print.Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.