Cell polarity proteins promote macropinocytosis in response to metabolic stress

Guillem Lambies, Szu-Wei Lee, Karen Duong-Polk, Pedro Aza-Blanc, Swetha Maganti, Cheska M. Galapate, Anagha Deshpande, Aniruddha J. Deshpande, David A. Scott, David W. Dawson and Cosimo Commisso ()
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Guillem Lambies: Sanford Burnham Prebys Medical Discovery Institute
Szu-Wei Lee: Sanford Burnham Prebys Medical Discovery Institute
Karen Duong-Polk: Sanford Burnham Prebys Medical Discovery Institute
Pedro Aza-Blanc: Sanford Burnham Prebys Medical Discovery Institute
Swetha Maganti: Sanford Burnham Prebys Medical Discovery Institute
Cheska M. Galapate: Sanford Burnham Prebys Medical Discovery Institute
Anagha Deshpande: Sanford Burnham Prebys Medical Discovery Institute
Aniruddha J. Deshpande: Sanford Burnham Prebys Medical Discovery Institute
David A. Scott: Sanford Burnham Prebys Medical Discovery Institute
David W. Dawson: David Geffen School of Medicine at University of California Los Angeles
Cosimo Commisso: Sanford Burnham Prebys Medical Discovery Institute

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract Macropinocytosis has emerged as a scavenging pathway that cancer cells exploit to survive in a nutrient-deprived microenvironment. Tumor cells are especially reliant on glutamine for their survival, and in pancreatic ductal adenocarcinoma (PDAC) cells, glutamine deficiency can enhance the stimulation of macropinocytosis. Here, we identify the atypical protein kinase C (aPKC) enzymes, PKCζ and PKCι, as regulators of macropinocytosis. In normal epithelial cells, aPKCs associate with the scaffold proteins Par3 and Par6 to regulate cell polarity, affecting several targets, including the Par1 kinases and we find that each of these proteins is required for macropinocytosis. Mechanistically, aPKCs are regulated by EGFR signaling or by the transcription factor CREM to promote the Par3 relocation to microtubules, facilitating macropinocytosis in a dynein-dependent manner. Importantly, cell fitness impairment caused by aPKC depletion is rescued by the restoration of macropinocytosis and aPKCs support PDAC growth in vivo. Our findings enhance our understanding of the mechanistic underpinnings that control macropinocytic uptake in the context of metabolic stress.

Date: 2024
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DOI: 10.1038/s41467-024-54788-9

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