title: SOX2 and PI3K Cooperate to Induce and Stabilize a Squamous-Committed Stem Cell Injury State during Lung Squamous Cell Carcinoma Pathogenesis.
abstract: Although cancers are considered stem cell diseases, mechanisms involving stem cell alterations are poorly understood. Squamous cell carcinoma (SQCC) is the second most common lung cancer, and its pathogenesis appears to hinge on changes in the stem cell behavior of basal cells in the bronchial airways. Basal cells are normally quiescent and differentiate into mucociliary epithelia. Smoking triggers a hyperproliferative response resulting in progressive premalignant epithelial changes ranging from squamous metaplasia to dysplasia. These changes can regress naturally, even with chronic smoking. However, for unknown reasons, dysplasias have higher progression rates than earlier stages. We used primary human tracheobronchial basal cells to investigate how copy number gains in SOX2 and PIK3CA at 3q26-28, which co-occur in dysplasia and are observed in 94% of SQCCs, may promote progression. We find that SOX2 cooperates with PI3K signaling, which is activated by smoking, to initiate the squamous injury response in basal cells. This response involves SOX9 repression, and, accordingly, SOX2 and PI3K signaling levels are high during dysplasia, while SOX9 is not expressed. By contrast, during regeneration of mucociliary epithelia, PI3K signaling is low and basal cells transiently enter a SOX2LoSOX9Hi state, with SOX9 promoting proliferation and preventing squamous differentiation. Transient reduction in SOX2 is necessary for ciliogenesis, although SOX2 expression later rises and drives mucinous differentiation, as SOX9 levels decline. Frequent coamplification of SOX2 and PIK3CA in dysplasia may, thus, promote progression by locking basal cells in a SOX2HiSOX9Lo state with active PI3K signaling, which sustains the squamous injury response while precluding normal mucociliary differentiation. Surprisingly, we find that, although later in invasive carcinoma SOX9 is generally expressed at low levels, its expression is higher in a subset of SQCCs with less squamous identity and worse clinical outcome. We propose that early pathogenesis of most SQCCs involves stabilization of the squamous injury state in stem cells through copy number gains at 3q, with the pro-proliferative activity of SOX9 possibly being exploited in a subset of SQCCs in later stages.
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Bo Ram
authors.initials: BR
authors.lastname: Kim
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Emily
authors.initials: E
authors.lastname: Van de Laar
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Michael
authors.identifier: http://orcid.org/0000-0001-8980-8783
authors.initials: M
authors.lastname: Cabanero
authors.affiliation: Division of Thoracic Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Tarumi
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hasenoeder
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Dennis
authors.initials: D
authors.lastname: Wang
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Carl
authors.initials: C
authors.lastname: Virtanen
authors.affiliation: Division of Thoracic Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Takaya
authors.identifier: http://orcid.org/0000-0003-4328-9345
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Bizhan
authors.initials: B
authors.lastname: Bandarchi
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Shingo
authors.identifier: http://orcid.org/0000-0003-1133-3313
authors.initials: S
authors.lastname: Sakashita
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Nhu An
authors.initials: NA
authors.lastname: Pham
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Sharon
authors.initials: S
authors.lastname: Lee
authors.affiliation: Division of Thoracic Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Shaf
authors.initials: S
authors.lastname: Keshavjee
authors.affiliation: Division of Thoracic Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Thomas K
authors.identifier: http://orcid.org/0000-0002-3235-9208
authors.initials: TK
authors.lastname: Waddell
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ming-Sound
authors.initials: MS
authors.lastname: Tsao
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Nadeem
authors.initials: N
authors.lastname: Moghal
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D002454:Cell Differentiation; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000502:physiology*; D015398:Signal Transduction; D014132:Trachea / Q000473:pathology
chemical_list: C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D019869:Phosphatidylinositol 3-Kinases