Tumor suppressors Sav/scrib and oncogene ras regulate stem‐cell transformation in adult Drosophila malpighian tubules

Abstract

An increasing body of evidence suggests that tumors might originate from a few transformed cells that share many properties with normal stem cells. However, it remains unclear how normal stem cells are transformed into cancer stem cells. Here, we demonstrated that mutations causing the loss of tumor suppressor Sav or Scrib or activation of the oncogene Ras transform normal stem cells into cancer stem cells through a multistep process in the adult Drosophila Malpighian Tubules (MTs). In wild-type MTs, each stem cell generates one self-renewing and one differentiating daughter cell. However, in flies with loss-of-function sav or scrib or gain-of-function Ras mutations, both daughter cells grew and behaved like stem cells, leading to the formation of tumors in MTs. Ras functioned downstream of Sav and Scrib in regulating the stem cell transformation. The Ras-transformed stem cells exhibited many of the hallmarks of cancer, such as increased proliferation, reduced cell death, and failure to differentiate. We further demonstrated that several signal transduction pathways (including MEK/MAPK, RhoA, PKA, and TOR) mediate Rasṕ function in the stem cell transformation. Therefore, we have identified a molecular mechanism that regulates stem cell transformation, and this finding may lead to strategies for preventing tumor formation in certain organs.

The adult Drosophila gastric and stomach organs are maintained by a multipotent stem cell pool at the foregut/midgut junction in the cardia (proventriculus)

“…The gut was dissected and stained as described previously. 36,67,[69][70][71][72] Confocal images were obtained using the Zeiss LSM510 system and processed with Adobe Photoshop CS2. The following antibodies were used: rabbit anti-b-gal (1:1000; Cappel), mouse anti-b-gal (1:100; Promega), rabbit anti-Odd (1:400; gift from J. Skeath), rabbit anti-MEF2 (1:1000; gift from B. Patterson), anti-Dve (1:1000; gift from F. Matsuzaki), mouse anti-Armadillo N7A1 [1:4; Developmental Studies Hybridoma Bank (DSHB)], mouse anti-Na/K ATPase a-subunit a5 (1:50; DSHB), mouse anti-Fu (1:100; DSHB), mouse anti-Ptc (1:100; DSHB), mouse antiBrdU (1:100; BD Biosciences or Invitrogen), rabbit anti-GFP (1:200; Invitrogen), and mouse anti-GFP (1:100; Invitrogen), chicken anti-GFP (Abcam), and rabbit anti-RFP (Invitrogen).…”

The Male Stem Cell Niche: Insights from Drosophila and Mammalian Model Systems

“…Suppressor of cytokine signaling 36E (Socs36E) suppresses Jak-Stat signaling in the CySCs preventing them from outcompeting the GSCs and thereby maintains the proper balance of GSCs and CySCs, in a manner that depends on the adhesion protein integrin [56,73]. Downstream of the JAK-STAT pathway in the Drosophila testis is the recently identified Slit-Roundabout 2 (Robo2) signaling pathway, which provides new information on how CySCs compete for occupying the niche [74].…”

“…The Janus-kinase transducer and activator of transcription (JAK-STAT) pathway was the first signaling pathway found to regulate GSC and CySC maintenance in the Drosophila testis [6,7]. The hub cells secrete the ligand Unpaired (Upd), which activates the JAK-STAT pathway in adjacent GSCs and CySCs [6,7,56]. In the absence of JAK-STAT signaling the GSCs differentiate and are unable to self-renew, whereas ectopic expression of upd in the germline greatly expands the population of GSCs and CySCs in adult as well as in larval testes [6,7].…”

Aging of Intestinal Stem Cells in Drosophila Melanogaster

“…These cells are capable of selfrenewal and give rise to progenitors that can differentiate in all the cell types that compose the tubule (i.e., renalcytes, principal cells, and stellate cells). The mechanisms that control SC proliferation and differentiation in this lineage are starting to be elucidated (Singh et al 2007 ;Zeng et al 2010 ). However, the impact of aging on the maintenance and turnover of this tissue remains unknown.…”