Compression-induced dedifferentiation of adipocytes promotes tumor progression

Abstract

Dysregulated physical stresses are generated during tumorigenesis that affect the surrounding compliant tissues including adipocytes. However, the effect of physical stressors on the behavior of adipocytes and their cross-talk with tumor cells remain elusive. Here, we demonstrate that compression of cells, resulting from various types of physical stresses, can induce dedifferentiation of adipocytes via mechanically activating Wnt/β-catenin signaling. The compression-induced dedifferentiated adipocytes (CiDAs) have a distinct transcriptome profile, long-term self-renewal, and serial clonogenicity, but do not form teratomas. We then show that CiDAs notably enhance human mammary adenocarcinoma proliferation both in vitro and in a xenograft model, owing to myofibrogenesis of CiDAs in the tumor-conditioned environment. Collectively, our results highlight unique physical interplay in the tumor ecosystem; tumor-induced physical stresses stimulate de novo generation of CiDAs, which feedback to tumor growth.

Tailoring Cellular Function: The Contribution of the Nucleus in Mechanotransduction

“…They found that the expression of the Ras V12 oncogene promotes tumor progression by altering cell mechanics and then allowing cell division also under severe mechanical confinement, while normal cells displayed mitotic arrest or chromosome segregation errors ( Matthews et al, 2020 ). Using polyacrylamide gels of different stiffness to confine cells (i.e., encapsulated in Matrigel), Li et al (2020) showed that compression, together with osmotic pressure and substrate stiffness, leads to adipocyte reprogramming into multipotent cell lineage and enhances human mammary adenocarcinoma cell proliferation.…”

“…A crucial milestone in the field was the discovery that cell stiffness, reflecting the stiffness of the surrounding microenvironment ( Discher et al, 2005 ), could regulate both tumorigenesis and cancer cell proliferation through the activation of the transcription factor YAP ( Dupont et al, 2011 ). Moreover, tissue mechanical properties have been linked to tumor progression ( Mouw et al, 2014 ; Nam et al, 2019 ), metastasis formation ( Liu et al, 2017 ; Rice et al, 2017 ), and dedifferentiation toward malignant phenotypes ( Li et al, 2020 ). All these findings underlie a tight connection between mechanically induced cytoskeletal modifications and nuclear structural elements, whose properties then affect gene expression profile and cancer cell behavior.…”

Adipogenesis in Different Body Depots and Tumor Development

“…Interestingly, tumor-provoked physical stresses can induce adipocyte dedifferentiation into a state similar to MSCs, termed as the compression-induced dedifferentiation of adipocytes, characterized by a clonogenic and multilineage differentiation capacity in vitro (Li et al, 2020). However, this observation needs to be validated in human cancer in vivo, considering that ASCs obtained from breast tumor patients display an impaired adipogenic capability (Rey et al, 2019).…”

A flexible micro-piston device for mechanical cell stimulation and compression in microfluidic settings

“…As a result, the application of mechanical compression on living cells, such as cancerous [5,[9][10][11][12][13][14][15][16][17][18][19], non-cancerous and stromal cells [20][21][22], neurons [23] and chondrocytes [24], has gained importance in recent years. Compression applied on cancer types, such as breast [5,16,18,19], brain [13], pancreatic [9] and ovarian [17,25] cancer cells, resulted in more invasive and metastatic forms. While indicative, previous studies all point out the need for further investigations to understand the e↵ect of compressive mechanical stimuli in metastasis of di↵erent cancer types, for example ovarian cancer [17,25,26].…”