Hyaluronan driven by epithelial aPKC deficiency remodels the microenvironment and creates a vulnerability in mesenchymal colorectal cancer

Martínez-Ordóñez, Anxo; Durán, Abraham Madroñal; Ruíz-Martínez, Marc; Cid-Diaz, Tania; Zhang, Xiao; Han, Qixiu; Kinoshita, Hiroto; Muta, Yu; Linares, Juan F.; Kasashima, Hiroaki; Nakanishi, Yuki; Omar, Mohamed A.A.; Nishimura, Shigeo; Ávila, Humberto; Yashiro, Masakazu; Maeda, Kiyoshi; Pannellini, Tania; Pigazzi, Alessio; Inghirami, Giorgio; Marchionni, Luigi; Sigal, Darren; Diaz‐Meco, María T.; Moscat, Jorge

doi:10.1016/j.ccell.2022.11.016

Cited by 21 publications

(33 citation statements)

References 79 publications

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“… 52 In CRC, trophoblasts were reported to produce hyaluronan, which induces mesenchymal phenotype with a poor prognosis. 53 Furthermore, some soluble factors released by fibroblasts were also reported to drive the cell fate conversion toward a fetal/regenerative/revival state in murine CRC models. 54 In addition, a previous report showed that a fetal/regenerative/revival state induced by CAFs was associated with chemoresistance.…”

Section: Discussionmentioning

confidence: 99%

Discovery of non-genomic drivers of YAP signaling modulating the cell plasticity in CRC tumor lines

Ogasawara,

Kano,

Yoneyama

et al. 2024

iScience

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Section: Discussionmentioning

confidence: 99%

Discovery of non-genomic drivers of YAP signaling modulating the cell plasticity in CRC tumor lines

Ogasawara,

Kano,

Yoneyama

et al. 2024

iScience

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“…These tumors showed, like in humans, a preference for the proximal location in the colon and a significantly large proportion progressed to intramucosal and even invasive adenocarcinoma, which contained areas of poorly differentiated or signet-ring cell carcinomas with severe desmoplastic change indicating the highly aggressive nature of those tumors, which were also immune-excluded 14 . The desmoplastic response in these aPKC-deficient serrated tumors was characterized by a profound remodeling of the fibroblast compartment with an accumulation of collagen and hyaluronan, recapitulating the most salient features of human mesenchymal (m)CRC 14 , 15 .…”

Section: Introductionmentioning

confidence: 96%

Enhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis

Muta,

Linares,

Martinez-Ordoñez

et al. 2023

Nat Commun

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The metabolic and signaling pathways regulating aggressive mesenchymal colorectal cancer (CRC) initiation and progression through the serrated route are largely unknown. Although relatively well characterized as BRAF mutant cancers, their poor response to current targeted therapy, difficult preneoplastic detection, and challenging endoscopic resection make the identification of their metabolic requirements a priority. Here, we demonstrate that the phosphorylation of SCAP by the atypical PKC (aPKC), PKCλ/ι promotes its degradation and inhibits the processing and activation of SREBP2, the master regulator of cholesterol biosynthesis. We show that the upregulation of SREBP2 and cholesterol by reduced aPKC levels is essential for controlling metaplasia and generating the most aggressive cell subpopulation in serrated tumors in mice and humans. Since these alterations are also detected prior to neoplastic transformation, together with the sensitivity of these tumors to cholesterol metabolism inhibitors, our data indicate that targeting cholesterol biosynthesis is a potential mechanism for serrated chemoprevention.

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“…Investigation of a large cohort of CRC specimens revealed that low levels of aPKC correlate with hyaluronic acid (HA) stromal deposition. Patients with low aPKC+high HA values had the worse prognosis ( Martinez-Ordonez et al, 2022 ; Fig. 3 C ).…”

Section: Introductionmentioning

confidence: 99%

“…HA controls endothelial remodeling, cancer-associated fibroblast phenotype, and immune cell infiltration. Mouse models revealed aPKC depletion causes the overexpression of HA synthase, and drug treatment that degrades HA restores a less permissive tumor ( Martinez-Ordonez et al, 2022 ). Whether aPKC controls HA synthesis and secretion through its cell polarity function remains to be explored.…”

Section: Introductionmentioning

confidence: 99%

“…Loss of aPKCι and aPKCζ in intestinal stem cells promotes serrated colorectal cancer formation by preventing CD8 + T cells from penetrating the tumors. It also stimulates the presence of immunosuppressive CD4 + regulatory T cells and PD-L1 expressing myeloid-derived suppressor cells (MDSCs; Martinez-Ordonez et al, 2022 ; Nakanishi et al, 2018 ). However, this effect may be tissue-specific.…”

Section: Introductionmentioning

confidence: 99%

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Cell polarity changes in cancer initiation and progression

Peglion,

Etienne-Manneville

2023

Journal of Cell Biology

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Cell polarity, which consists of the morphological, structural, and functional organization of cells along a defined axis, is a feature of healthy cells and tissues. In contrast, abnormal polarity is a hallmark of cancer cells. At the molecular level, key evolutionarily conserved proteins that control polarity establishment and maintenance in various contexts are frequently altered in cancer, but the relevance of these molecular alterations in the oncogenic processes is not always clear. Here, we summarize the recent findings, shedding new light on the involvement of polarity players in cancer development, and discuss the possibility of harnessing cell polarity changes to better predict, diagnose, and cure cancers.

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Hyaluronan driven by epithelial aPKC deficiency remodels the microenvironment and creates a vulnerability in mesenchymal colorectal cancer

Cited by 21 publications

References 79 publications

Discovery of non-genomic drivers of YAP signaling modulating the cell plasticity in CRC tumor lines

Discovery of non-genomic drivers of YAP signaling modulating the cell plasticity in CRC tumor lines

Enhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis

Cell polarity changes in cancer initiation and progression

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