Cancer cells enter dormancy after cannibalizing mesenchymal stem/stromal cells (MSCs)

Abstract

Patients with breast cancer often develop malignant regrowth of residual drug-resistant dormant tumor cells years after primary treatment, a process defined as cancer relapse. Deciphering the causal basis of tumor dormancy therefore has obvious therapeutic significance. Because cancer cell behavior is strongly influenced by stromal cells, particularly the mesenchymal stem/stromal cells (MSCs) that are actively recruited into tumor-associated stroma, we assessed the impact of MSCs on breast cancer cell (BCC) dormancy. Using 3D cocultures to mimic the cellular interactions of an emerging tumor niche, we observed that MSCs sequentially surrounded the BCCs, promoted formation of cancer spheroids, and then were internalized/degraded through a process resembling the well-documented yet ill-defined clinical phenomenon of cancer cell cannibalism. This suspected feeding behavior was less appreciable in the presence of a rho kinase inhibitor and in 2D monolayer cocultures. Notably, cannibalism of MSCs enhanced survival of BCCs deprived of nutrients but suppressed their tumorigenicity, together suggesting the cancer cells entered dormancy. Transcriptome profiles revealed that the resulting BCCs acquired a unique molecular signature enriched in prosurvival factors and tumor suppressors, as well as inflammatory mediators that demarcate the secretome of senescent cells, also referred to as the senescence-associated secretory phenotype. Overall, our results provide intriguing evidence that cancer cells under duress enter dormancy after cannibalizing MSCs. Importantly, our practical 3D coculture model could provide a valuable tool to understand the antitumor activity of MSCs and cell cannibalism further, and therefore open new therapeutic avenues for the prevention of cancer recurrence.

Cancer cell cannibalism and the SASP: Ripples in the murky waters of tumor dormancy

“…7 Overall, this might explain why the cannibalistic BCCs in our study recovered their ability to proliferate after just a few days in culture but continued to express SASP factors such as interleukin-1 a (IL1A), C-X-C motif chemokine ligand 8 (CXCL8), CXCL1, C-C motif chemokine ligand 20 (CCL20), and SERPINE1, among other molecules, for at least 5 weeks in vivo. 3 Taken together, our results indicated that BCC cannibalism of BM-MSCs supports certain facets of tumor dormancy (Fig. 1); although a direct causal relationship in patients has been challenging to elucidate as unique MSC markers in vivo are unknown.…”

“…3 This conclusion was drawn from compelling data demonstrating that, after consuming BMMSCs, cannibalistic BCCs became highly resistant to stresses imposed by nutrient deprivation and chemotherapy but, strikingly, their ability to form tumors in mice was greatly diminished. 3 In general, cellular cannibalism is a term used to describe a distinct phagocytic-like process in which one cell engulfs and often eliminates neighboring intact cells. 4 Although the phenomenon was first demonstrated over a century ago and has been observed frequently in cancer tissue, 4 its impact on tumor progression has only recently received substantial attention.…”

“…1). 3 Interestingly, the resulting cannibalistic BCCs produced an array of cytokines/chemokines and proteases commonly secreted by senescent cells as part of the senescence-associated secretory phenotype (SASP). 7,8 Historically, cellular senescence, which by definition is linked to permanent cell cycle arrest, was considered a mechanism of tumor suppression and aging, although it is now acknowledged to be important for embryogenesis and injury repair.…”

Manger et dormir

“…Afin d'apprécier les interactions entre des cellules cancéreuses mammaires connues pour être douées d'activités cannibales [5] et des cellules mésenchy-mateuses obtenues à partir du stroma de la moelle osseuse [4], T.J. Bartosh et ses collaborateurs (T exas A&M College of Medicine, Temple, Texas, États-Unis) ont observé, au cours d'expériences de culture cellulaire en trois dimensions, la capacité des cellules mésenchymateuses à interagir avec les cellules cancéreuses, à s'organiser avec ces dernières sous la forme de sphéroïdes et à finalement être « mangées » par les cellules cancéreuses. Lors de ces expériences, les auteurs soulignent la capacité des cellules cancéreuses à internaliser des cellules mésenchymateuses vivantes et à les éliminer selon un processus de mort cellulaire atypique.…”

“…Il a ainsi été proposé que des cellules cancéreuses dont l'activité mitotique est plus faible, les « cellules dormantes », seraient moins sensibles aux thérapies anticancéreuses et pourraient, à la suite de leur « réveil », être à l'origine de l'échappement des tumeurs aux traitements et de la rechute tumorale. Le cannibalisme cellulaire est une nouvelle forme de mort cellulaire au cours de laquelle une cellule vivante « mange » une autre cellule vivante et l'élimine après l'avoir internalisée [2,3] ; ce processus biologique a récemment été identifié comme pouvant conduire à la dormance cellulaire [4].…”